We plan to conduct a genome-wide association study of young (<50 years) invasive female breast cancer to identify new genes responsible for young cases who are negative for BRCA1 and BRCA2 gene mutations. This collaborative study will exploit the availability of biological samples and epidemiological data from 2,330 population-based, individually matched case-control pairs ascertained by large breast cancer study resources in Australia, Canada, the US and Germany. We will focus on early-onset BRCA1- and BRCA2-negative invasive cases because this group has high public health importance and high likelihood of harboring unidentified breast cancer genes. To enhance cost-efficiency and validity, the study will proceed in two phases. Phase I will genotype and analyze population-based samples of 1,500 non-Hispanic Caucasian matched case-control pairs. We will perform Phase I in two stages. In Stage 1, we will genotype and analyze 1,000 case-control pairs, using the Affymetrix 500k SNP array augmented by the ParAllele non-synonymous 20k cSNP panel. In Stage 2, we will genotype the remaining 500 case-control pairs only for the SNPs identified as promising in Stage 1. We will then analyze these SNPs using all 1,500 case-control pairs, adjusting for established breast cancer risk factors. Phase II will genotype and analyze an independent set of 830 population-based sister case-control pairs for all promising SNPs from Phase I and also the surrounding haplotype-tagging and functional SNPs in the haplotypes containing these SNPs. Phase II provides robustness against false positives due either to confounding by population structure or to multiple comparisons in Phase I analyses. This genome-wide association study offers several strengths, including the availability of large numbers of population-based, well-matched young cases and controls, the ability to control confounding by population structure using a robust sister-pair design, and the extended genomic coverage provided by the combined Affymetrix and ParAllele high-density SNP panels. In conclusion, this research aims to identify new genes for early-onset breast cancer, which is a major source of morbidity, mortality and loss of life expectancy throughout the world.